Outcomes of people with TB reported to the WHO Global Clinical Platform of COVID-19

SUMMARY BACKGROUND TB is a leading infectious cause of death worldwide. The COVID-19 pandemic raised concerns that the burden of TB disease and death would increase due to the synergy between the two conditions. METHODS We used individual-level data submitted to the WHO Global Clinical Platform for COVID-19 on hospitalised patients to explore associations of TB with mortality using multivariable logistic regression. RESULTS Data were available from 453,233 persons with COVID-19 and known TB status and mortality outcomes from 62 countries (96% SARS-CoV-2 test-positive). Of these, 48% were male, and the median age was 53 years (IQR 38–67). There were 8,214 cases with current TB reported by 46 countries, mainly from Africa. Of people with current TB, 31.4% were admitted with severe illness, and 24.5% died. Current TB was independently associated with higher mortality when adjusted for age, sex, HIV status, illness severity at hospital admission, and underlying conditions (adjusted RR 1.47, 95% CI 1.35–1.61). CONCLUSION Current or past TB were independent risk factors for in-hospital mortality regardless of illness severity at admission. Caveats for interpretation include changes during the data collection period (viral variation, vaccination coverage) and opportunistic sampling. However, the platform exemplifies how timely, coordinated global reporting can inform our understanding of health emergencies and the vulnerable populations affected.

undernourishment.Early analysis of evidence suggested that both current and past TB increased the risk of dying in COVID-19 patients and that older age and diabetes were also associated with poorer outcomes in COVID-19 as in TB. 3 In many high TB burden settings, access to the COVID-19 vaccine was minimal, and vaccine prioritisation for vulnerable subpopulations was therefore critical.
Disease modelling described that a putative 25% reduction in TB detection for 6 months due to COVID-19-related disruptions would lead to a 26% increase in TB deaths, negating all progress made since 2012. 4his scenario was consistent with WHO data, which showed substantial reductions in TB notification sustained over successive months in 2020 in many high TB-burden countries as COVID-19 measures were introduced.6][7] Globally, new TB notifications reported to the WHO fell by 18% from 7.1 million in 2019 to 5.8 million in 2020.This increased to 7.5 million new TB notifications in 2022, showing that there has been a good post-COVID recovery in access to and provision of health services in many (but not all) countries.This may reflect, at least in part, a backlog of delayed TB diagnoses related to pandemic-associated disruption.
Identifying risk factors for severe or fatal COVID-19 can help public health authorities prioritise populations and preventive interventions.WHO created the Global Clinical Platform on COVID-19 shortly after the pandemic was declared in April 2020. 8This platform consolidates anonymised individual-level clinical data of hospitalised patients with suspected or confirmed COVID-19 from health facilities worldwide.We used the data from this platform to explore the association between TB disease-past and current-and severe or fatal outcomes in hospitalised COVID-19 patients.

Data sources
Data were contributed by Ministries of Health, research networks, and health facilities using a standardised Case Report Form (CRF) and data dictionary. 8Additional data were solicited from research networks, health facilities, and authors of published articles identified by continued scanning of literature and imported from their existing datasets.The platform allowed retrospective or prospective data collection.
The standardised set of variables described patient data at hospital admission, daily review, and hospital discharge.Each country dataset included demographics, pregnancy status, vital signs, anthropometrics, past medical and medication history, clinical features, laboratory test results, therapeutics, use of oxygen, use of mechanical ventilation, complications arising due to COVID-19, and clinical outcomes (discharge, death, transfer to another facility, intensive care admission, and ongoing hospitalisation).

Study design and population
All patients admitted to a healthcare facility with laboratory-confirmed or clinically suspected COVID-19

Statistical analysis
Patient characteristics were described by current or past TB disease status.Missing data were presented as counts and excluded from the calculation of proportions.Length of stay data were presented with medians and interquartile ranges (IQRs) and compared with the Wilcoxon rank-sum test.In-hospital deaths were defined as deaths occurring during hospitalisation.Case-fatality ratio (CFR) was calculated from the number of in-hospital deaths as a proportion of people dying in the hospital plus those discharged alive.Patients with other outcomes (palliative discharge, still hospitalised and transfer)-which represent 2.5% of admissions-were excluded from the CFR calculation.Multivariable log-binomial regression was used to evaluate the independent association of current TB with in-hospital mortality, using adjusted risk ratios (aRRs) and 95% confidence intervals (95% CIs).A P-value under 0.05 was considered statistically significant.The estimation of variance in the model was adjusted for potential clustering at the country level.
The following factors were a priori included in the model: age, sex, severity of COVID-19 disease, HIV status, and other comorbidities (chronic cardiac disease, diabetes, hypertension, chronic pulmonary disease, and asthma).Sensitivity analysis was done by including the history of TB disease in the final model, with stratification by HIV status to explore the effect modification of mortality risk.Analyses were conducted in R v4.3.1 (R Computing, Vienna, Austria). 9

Ethics clearance
The analysis described in this paper conforms to the Platform's analysis plan.This plan was exempted from ethics review clearance by the WHO Research Ethics Review Committee (ERC; Geneva, Switzerland) because we used anonymised clinical surveillance data.Ethics clearance was obtained, where necessary, by institutional or national bodies contributing data.

Patient characteristics
Anonymised data were available for 453,233 COVID-19 hospital admissions from 62 countries with known TB status (Table 1, Figure 1).In 96%, a SARS-CoV-2 test was reported to be positive.Patient characteristics stratified by TB status are presented in Table 1.Within

DISCUSSION
Our analysis of the Global Clinical Platform on COVID-19 explored links between TB and severe or fatal outcomes in hospitalised COVID-19 patients.We found current TB to be an independent risk factor for in-hospital mortality regardless of illness severity at hospital admission and quantified this risk.Among patients dying in the first week after admission, the time to death was shorter in people with current TB.
The potential for SARS-CoV-2 and TB interaction worsening outcomes has been previously suggested.However, a systematic review from 2022 found limited evidence base addressing the impact of TB on COVID-19 death and unfavourable outcomes. 10Similarly, a 2023 systematic review of TB and SARS-CoV-2 coinfection demonstrated low quality and conflicting evidence on the effect of immunomodulating treatment on TB outcomes and COVID-19-related outcomes (progression to severe or critical COVID-19 or death). 11There were no studies specifically designed to address these questions.
Our subsequent findings suggest that in hospitalised COVID-19 patients, the presence of concurrent TB increases the risk of death by about 50%.Past TB also represents an increased risk.The potential implications for health policy include the prioritisation of COVID-19 vaccination in people with current or past TB.It may also be expedient to test all TB patients for SARS-CoV-2 early on when there is known virus transmission in the community.The quick onset of death after hospitalisation may suggest a need for earlier admission to hospital care, more triage, and close care following admission.
TB remains a major global public health challenge.It is a disease firmly rooted in poverty and associated with a shortage of universal health care.The advent of COVID-19 represented another potential threat to efforts to curb TB.COVID-19 has had a profound impact on global poverty: in 2021, it was estimated that close to 100 million people worldwide were living on less than US$1.90 per day due to the pandemic. 12The global epidemic of TB is influenced by different social and health-related factors, particularly undernourishment, HIV infection, alcohol use disorders, smoking, and diabetes, many of which are adversely influenced by poverty.Similarly to people with TB, COVID-19 patients risk poorer outcomes if they are older and have diabetes or HIV.
An earlier study using the WHO Global Clinical Platform analysed records from 38 countries available until July 2021, concluding that HIV was an independent risk factor for both severe COVID-19 at admission and in-hospital mortality. 13The findings have informed WHO immunisation policy, which prioritises vaccination for people living with HIV.In our analysis, there was limited effect modification by HIV status, implying that the risk of worse outcomes in COVID-19 patients with TB was present in both people with HIV and those without.
Despite the utility for public health, these data have some limitations.No external data validation was possible after submission beyond coherency checking.Definitions of current and past TB may have differed between countries.Data completion was variable, limiting the analysis particularly concerning factors plausibly, or known to be, associated with the outcomes (e.g., HIV viral load).Potentially useful variables such as CD4 counts, TB diagnostics or treatment used, nutritional status, income, quantification of alcohol intake,  diabetes control, and other socioeconomic determinants were not included to keep the CRF brief.The high proportion of patients with current TB in some cohorts might indicate a reporting bias to the platform (selection or ascertainment bias) and certainly reflect a geographical over-representation of some countries, for example, South Africa, where data collection and submission were extensive.Secular changes such as predominant circulating viral strains, vaccination coverage, and sampling criteria may affect results over time, but we have reported the whole dataset.The absence of information about postdischarge survival may have led to an underestimation of overall mortality, although this would probably be independent of current TB status.
In conclusion, this multi-country individual-level data analysis shows that TB is independently associated with an increased risk of presenting with severe or critical COVID-19 at hospital admission and an increased likelihood of in-hospital mortality.The analysis demonstrates that a unified data collection platform can continuously inform public health action.Within the framework of pandemic preparedness, provisions must be made to strengthen the collection and timely sharing of data with the WHO, including data on health conditions like TB, which are critical drivers of disease burden and death.

Figure 2 .
Figure 2. Adjusted risk ratios* of in-hospital mortality among COVID-19 patients on the WHO Global Clinical Platform for COVID-19.*From multivariable log-binomial regression of pooled data, 2020-2023.The following factors were a priori included in the model: age, sex, severity of COVID-19 disease, HIV status, and other comorbidity (chronic cardiac disease, diabetes, hypertension, chronic pulmonary disease, and asthma).

Table 1 .
Characteristics of hospitalised COVID-19 cases on the WHO Global Clinical Platform for COVID-19 by TB status.
from 01 January 2020 to 31 May 2023 were eligible for inclusion.Cases were defined as mild/moderate or severe/critical according to a modified definition from the WHO Clinical Management Guidelines of COVID-19.

Table 2 .
CFRs and aRRs* of in-hospital mortality by subgroup of COVID-19 patients, WHO Global Clinical Platform for COVID-19.

Table 3 .
Time to discharge alive and time to death among hospitalised COVID-19 cases by TB status, WHO Global Clinical Platform for COVID-19.